Head and neck cancer (HNC) includes malignant tumors arising from a variety of sites in the upper aerodigestive tract (UADT), including the oral cavity, the pharynx, and the larynx. HNC represents the fifth most common malignancy worldwide. It was ranked as the eighth leading cause of cancer death in the world. In 2008, there were an estimated 48,000 new cases and more than 11,000 deaths of HNC in the United States. More than 90% of head and neck malignancies are squamous cell carcinoma (SCC), originating from the epithelium which lines the UADT. The incidence of head and neck squamous cell carcinoma (HNSCC) increases with age and is more common in men than in women. Tobacco and alcohol consumption are well established risk factors for HNSCC. However, a proportion of HNSCC occurs in nonsmokers and nondrinkers, suggesting the presence of other risk factors. Human papilloma virus (HPV) has been proven to be an etiologic factor for cervical cancer. HPV primarily infects the epithelium and induces benign as well as malignant lesions of the mucosa and skin. More than 70 types of HPV have been described. According to their implications in carcinogenesis, particularly the malignant progression of cervical tumors, HPV types were classified into high-risk (16, 18, 31,33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) and low-risk (6, 11, 26, 40, 42, 53, 54, 55, 57, 66, 83 and 84) groups. Low-risk types are associated with benign lesions such as warts, while infections with high-risk types progress to malignant lesions. High-risk HPV types 16 and 18 have been reported as the most prominent etiologic factors behind the development of cervical cancer. In recent decades, molecular and epidemiologic data have linked HPV with HNSCC. Although HPV type 16 alone was found to account for more than 90% of HPV-positive HNSCC and HPV type 18 is the second most common genotype, a variety of other high- and low-risk HPVs were also found to be present in HNSCC. In fact, the prevalence of other HPV genotypes (other than the 16 and 18) has been significantly underreported, either due to lack of sensitive viral detection methods used, type of specimen tested, and lack of actual testing for these non-HPV16 and non-HPV18 genotypes. Furthermore, the contribution of non-HPV16/18 genotypes as cofactors that participate in the oncogenic process has not been fully examined, nor has it been excluded that different HPV genotypes have different colonization and oncogenic potential in distinct oral tumor sites. Most HPV-associated HNSCC tend to occur in the oropharynx, with highest distribution in the tonsils. The proportion of HNSCC that are potentially HPV-related has been on the rise in the U.S., while the potentially HPV-unrelated HNSCC declined. Presence of HPV in HNSCC has been linked with sexual behaviors. Patients with HPV-positive HNSCC tend to be younger and free of smoking and drinking history, the majority of them are females. They also seem to have a better survival than the HPV-negative HNSCC patients, due to an increased radiocurability of HPV-positive tumors. Evidence supports the idea that HNSCC is a multifactorial disease with at least two, possibly distinct, pathways, one driven by tobacco and alcohol consumption, the other driven by HPV. The reported prevalence of HPV in HNSCC varied between 0-100% . This broad variation in HPV detection rates is attributable to tumor site, HPV detection method (polymerase chain-reaction (PCR), in situ hybridization (ISH), or Southern hybridization), specimen source and collection methods (swabs, brushings, mouthwash, fresh tissue, fixed tissue, etc.), use of HPV type specific vs. universal primers, and sample size and composition. PCR is consider more sensitive than the other testing methods. Small sample size and the inability to classify cases by anatomic subsite and to differentiate primary, recurrent, and metastatic tumors is likely to have contributed to the inconsistencies. The recognition of HPV as a major etiologic agent for HNSCC necessitates a new understanding of the diseases development and stimulates research in order to develop strategies for the screening, education, prevention, diagnosis, and treatment of HNSCC.